genome-guided introspection

On the genetics of epigenetics (part un)

Last year I dug a bit into the area of epigenetics (indexed here) and learned that the methylation (CH3) and acetylation (OCCH3) of genomic DNA & histones, respectively, can have dramatic effects on the structure of DNA and its accessibility to transcription factors – and hence – gene expression. Many of the papers I covered suggested that the environment can influence the degree to which these so-called “epigenetic marks” are covalently bonded onto the genome during early development. Thus, the thinking goes, the early environment can modulate gene expression in ways that are long-lasting – even transgenerational. The idea is a powerful one to be sure. And a scary one as well, as parents who read this literature, may fret that their children (and grandchildren) can be epigenetically scarred by early nutritional, physical and/or psycho-social stress. I must admit that, as a parent of young children myself, I began to wonder if I might be negatively influencing the epigenome of my children.

I’m wondering how much physical and/or social stress is enough to cause changes in the epigenome? Does the concern about epigenetics only apply to exposure to severe stress? or run of the mill forms of stress? How much do we know about this?

This year, I hope to explore this line of inquiry further. For starters, I came across a fantastic paper by Fraga et al., entitled, “Epigenetic differences arise during the lifetime of monozygotic twins” [doi:10.1073/pnas.0500398102]. The group carries out a remarkably straightforward and time honored approach – a twin study – to ask how much identical twins differ at the epigenetic level. Since identical twins have the same genome sequence, any differences in their physiology, behavior etc. are, strictly speaking, due to the way in which the environment (from the uterus to adulthood) shapes their development. Hence, the team of Fraga et al., can compare the amount and location of methyl (CH3) and acetyl (OCCH3) groups to see whether the environment has differentially shaped the epigenome.

An analysis of some 40 identical twin pairs from ages 3-74 years old showed that – YES – the environment, over time, does seem to shape the epigenome (in this case of lymphocytes). The most compelling evidence for me was seen in Figure 4 where the team used a method known as Restriction Landmark Genomic Scanning (RLGS) to compare patterns of methylation in a genome-wide manner. Using this analysis, the team found that older twin pairs had about 2.5 times as many differences as did the epigenomes of the youngest twin pairs. These methylation differences also correlated with gene expression differences (older pairs also had more gene expression differences) and they found that the individual who showed the lowest levels of methylation also had the highest levels of gene expression. Furthermore, the team finds that twin pairs who lived apart and had more differences in life history were more likely to have epigenetic differences. Finally, measures of histone acetylation seemed consistent with the gradient of epigenetic change over time and life-history distance.

Thus it seems that, as everyday life progresses, the epigenome changes too. So, perhaps, one does not need extreme forms of stress to leave long-lasting epigenetic marks on the genome? Is this true during early life (where the team did not see many differences between pairs)? and in the brain (the team focused mainly on lymphocytes)? Are the differences between twins due to the creation of new environmentally-mediated marks or the faulty passage of existing marks from dividing cell-to-cell over time? Will be fun to seek out information on this.